DESCRIPTION (Investigator's Abstract): Choroid plexus has a major role in regulating the composition of brain extracellular fluid. Recently, growth- factors have been identified in choroid plexus, an epithelium well known for its secretory function. Because peptides like fibroblast growth factor (FGF)-2 and transforming growth factor(TGF)- 1 have key roles in CNS ontogeny, and in the response to brain injury, there is the intriguing possibility that choroid plexus secretes growth factors into cerebrospinal fluid (CSF) for bulk flow distribution to target cells the developing or traumatized brain. There is a need to elucidate factors that regulate the composition of FGF-2 and TGF-B1 (and other isoforms) in CSF. We hypothesize that levels of these growth factors in CSF promote brain development, and repair after injury. However, deficient or excessive levels of FGF-2 and TGF- Betal may occur in aging or hydrocephalus, respectively. It seems reasonable to postulate that substantial alterations in CSF growth factor concentrations can markedly alter CSF dynamics, and thus brain function. Three models of Sprague-Dawley rats will be used: I) age progression (infant, young adult and aged animals), 2) hydrocephalus, and 3) transient forebrain ischemia (bilateral carotid occlusion). Our preliminary data indicate that infusion of an endogenous substance, i.e., FGF-2, into a lateral ventricle results in hydrocephalus. Overall, our strategy will be to infuse FGF-2 and TGF-p 1, with or without agents that interfere with the ability of these growth factors to act on their respective receptors. Responses to treatments will be characterized at levels of: a) expression of FGF-2 and TGF-Beta1 proteins and their receptors, b) ultrastructure of the cells surrounding CSF (choroid, ependyma, and arachnoid villi), and c) function (i.e., choroid plexus blood flow, ion transport and CSF secretion). The long-term goal is to gain an enhanced understanding of the role of FGF-2 and TGF Beta1 in brain extracellular fluid (CSF) in injury states, and in neurodegenerative diseases associated with aging.